Bivalirudin in Patients Undergoing PCI: State of Art and Future Perspectives.

Acute coronary syndrome (ACS) represents the most common cause of death worldwide. Percutaneous coronary intervention (PCI) is the management of choice in patients with ACS and occurrence of intra-procedural thrombotic complications are an independent predictor of mortality and other major adverse cardiovascular events in patients undergoing PCI. According to current guideline, anticoagulation therapy is indicated during PCI in order to reduce the risk of thrombotic complications such as stent thrombosis. Among currently available anticoagulant drugs, bivalirudin demonstrates a lower incidence of bleeding risk, despite it is associated with an increased risk of stent thrombosis. The aim of this paper is to discuss the pharmacology of bivalirudin and the clinical evidences of its use in patients undergoing PCI for ACS.


INTRODUCTION
Coronary artery disease (CAD) represents the most common cause of death worldwide. According to characteristic electrocardiographic modifications, ACS are classified in: ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina (UA) if cardiac biomarkers are negative 1 . PCI is the management of choice in patients with ACS 2,3 . The occurrence of intraprocedural thrombotic complications is an independent predictor of cardiovascular mortality and major adverse cardiovascular events (MACE) in patients undergoing PCI 4,5 and, according to current guideline, anticoagulation therapy is indicated, during PCI, in order to reduce this risk. Unfractionated heparin (UFH), low molecular weight heparin (LMWH) and fondaparinux, were considered the anticoagulants of choice for years, while, recently, bivalirudin, has been indicated in patients undergoing PCI 6 . The 2013 American College of Cardiology Foundation and American Heart Association guideline for management of patients with ST segment elevation myocardial infarction, recommends UFH with or without planned glycoprotein IIb/IIIa inhibitor (GPI) or bivalirudin as class I indication for patients undergoing primary PCI, with a preference for bivalirudin over UFH plus GPI in patients at high risk of bleeding (class IIa) 7 . The 2012 European Society of Cardiology guideline, however, recommend bivalirudin over UFH plus GPI (class I) but also LMWH (with or without GPI) over UFH (class IIb) 8 . Among currently available anticoagulant drugs, bivalirudin demonstrates a lower incidence of bleeding risk, despite it is associated with an increased risk of stent thrombosis. The aim of this paper is to discuss the pharmacology of bivalirudin and the clinical evidences of its use in patients undergoing PCI for an ACS.

II. PHARMACOLOGY OF BIVALIRUDIN
Bivalirudin is a transient and reversible thrombin inhibitor, preventing initiation and continuation of clot formation ( Figure 1). It is a semi synthetic peptide of 20-amino acid peptide (2,180 Da molecular weight) derived from Irudin and extracted from Hirudo medicinalis 9 , with an half-life of 25 minutes and a volume of distribution of 0.24 l/kg; after intravenous administration it has a complete and immediate bioavailability. Bivalirudin has a lack of binding to plasma proteins and about 20% is excreted unmodified in the urine; renal failure prolongs its half-time up to four hours. No pharmacokinetic modifications have been observed in different age or gender 10 (Table 1). Currently, the recommended dose for patients undergoing PCI is a bolus of 0.75 mg/kg followed by an infusion of 1.75mg/kg/h for the duration of the procedure 6 . Unfortunately, no specific antidote exists for bivalirudin intoxication/overdosage and hemodialysis, hemofiltration, or plasmapheresis seem to be helpful in case of overdosage 11 .   procedure). Primary efficacy outcome, defined as a composite of all-cause mortality, cerebrovascular accident, reinfarction, or unplanned target lesion revascularisation, and primary safety, defined as incidence of major bleeding were evaluated at 28 days 16 . GPI was administered with no significant differences in both groups, in presence of massive thrombus, slow or no-reflow, or a thrombotic complication (13% in the bivalirudin and 15% in the UFH group). The primary efficacy outcome at 28 days was prevalent in bivalirudin arm (8.7 vs. 5.7%; RR 1.52, 95% CI 1.09-2.13, p=0.01). Bivalirudin patients showed an higher reinfarction and revascularization rate (2.7 vs. 0.9%, p=0.004; 2.7 vs. 0.7%, p=0.001, respectively). These findings may be explained with the abrupt discontinuation of bivalirudin infusion as soon as angioplasty was terminated, thus increasing the incidence of stent thrombosis (3.4 vs. 0.9%, p= 0.001). No significant differences were observed in both groups in the primary safety outcome at 28 days. In order to evaluate efficacy and safety of the association between bivalirudin and prasugrel, compared with UFH and clopidogrel the Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 study was performed. BRAVE 4 was a randomized, open-label, multicenter trial, comparing prasugrel plus bivalirudin to clopidogrel plus UFH in 548 STEMI patients planned for primary PCI 17 . Aim of this study was test the hypothesis that in STEMI patients undergoing primary PCI, prasugrel plus bivalirudin therapy is superior to clopidogrel plus heparin in terms of net clinical outcome (the composite of death, recurrent myocardial infarction, unplanned infarct-related artery revascularization, stroke, definite stent thrombosis, or major bleeding). No significant difference between two groups in the composite ischemic endpoint, bleeding events, cardiac mortality, or definite stent thrombosis, were observed and, due to slow recruitment, the trial was prematurely stopped. The Bivalirudin in Acute Myocardial Infarction vs Heparin and GPI Plus Heparin Trial (BRIGHT) was performed to determine if bivalirudin is superior to UFH with or without tirofiban during primary PCI. BRIGHT was a multicenter, open-label, randomized trial, involving 2194 patients with acute myocardial infarction undergoing primary PCI (1925 patients with STEMI and 269 patients with NSTEMI). Patients were randomly assigned to receive bivalirudin with a post-PCI infusion (n = 735), heparin alone (n = 729), or UFH plus tirofiban with a post-PCI infusion (n = 730) 18 . Aim of the study was to determine if bivalirudin was superior to UFH alone or plus tirofiban during primary PCI in term of composite of all-cause mortality, reinfarction, target vessel revascularization, stroke, and any bleeding events at 30 days. Net adverse clinical events in patients treated with bivalirudin, UFH and UFH plus tirofiban were 8.8%, 13.2% and 17%, respectively (RR for bivalirudin vs. UFH 0.67, 95% CI 0.50-0.90, p=0.008). This finding was largely due to a reduction in bleeding events with bivalirudin, while no significant differences in major adverse cardiac, cerebral events or stent thrombosis among three groups were observed. Taken together these data demonstrated a lower incidence of bleeding with bivalirudin without any reduction on mortality. The Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) was a randomised, multicentre trial comparing transradial against transfemoral access in patients with ACS undergoing PCI. Patients were randomized (1:1) to radial or femoral access and to receive bivalirudin, stopped at the end of PCI or prolonged infusion for at least 4-6 hours, or UFH with provisional GPI 19 . The primary outcome was the composite of death, non-fatal myocardial infarction, or stroke, evaluated at 30 days. No significant differences were observed in patients treated with bivalirudin compared to patients treated with UFH (10.3 vs. 10.9%, p=0.45). Furthermore, patients in bivalirudin arm showed a lower rate of bleeding but an higher rate of stent thrombosis (1.4 vs. 2.5%, p=0.001; 1 vs. 0.6%, p=0.048, respectively). Interestingly, patients in bivalirudin arm showed lower rate of all cause mortality (1.7 vs. 2.3%, p=0.042). Thus, despite several randomized studies, the safety and efficacy of bivalirudin compared with UFH, with or without GPI, in patients with acute myocardial infarction undergoing PCI are still uncertain. Among all these randomized trials, bivalirudin showed a significant reduction of bleeding rate with an higher incidence of early stent thrombosis. However, when bivalirudin was administered up to 4 hours after the end of PCI, as in the BRIGHT trial, no differences in the incidence of early stent thrombosis were observed between bivalirudin and UFH arms, suggesting that a prolonged bivalirudin administration may significantly reduces the incidence of early stent thrombosis. Furthermore, as demonstrate in the EUROMAX trial, prolonging the low dose bivalirudin administration after PCI, reduces incidence of major bleeding, with a reduction in the overall mortality rate but an increased risk of stent thrombosis within the first 24 hrs post PCI. This finding is confirmed in our experience in more than 600 STEMI patients undergoing PCI and prolonged bivalirudin administration up to 40 hours after PCI (unpublished data . This study showed that abciximab and unfractionated heparin, as compared with bivalirudin, failed to reduce the rate of the primary end point and increased the risk of bleeding among patients with non-ST-segment elevation myocardial infarction undergoing PCI. These findings were confirmed at 1 year follow-up 24 . To evaluate the optimal adjunctive anticoagulation regimen for PCI in patients presenting ACS initially treated with fondaparinux, the SWITCH III trial was performed. SWITCH III was an open-label pilot trial comparing UFH to bivalirudin in patients presenting with ACS initially treated with fondaparinux and a Università degli Studi di Salerno loading dose of 600 mg of clopidogrel 25 . During PCI, patients were randomized to either bivalirudin or UFH therapy in a 1:1 fashion. GPI were used in 3.9% patients of bivalirudin and 12.2% patients of UFH group. The number of ischemic or bleeding events was very low and no significant differences were detected between groups. Current data suggest that bivalirudin treatment, compared to others anticoagulant drugs, in NSTEMI patients underwent PCI results in bleeding reduction with no differences in the rate of death, myocardial infarction or recurrent ischemia.

V. BIVALIRUDIN IN STABLE OR UNSTABLE ANGINA SETTING
Randomized trials testing the use of bivalirudin in the management of stable or unstable angina are listed in Table 4. The HIRULOG was a double blind trial enrolling patients with unstable angina or post-infarction angina undergoing urgent PCI 26 . Patients were randomized in two groups receiving either heparin or bivalirudin immediately before angioplasty. The primary end point was in hospital death, myocardial infarction, abrupt vessel closure, or rapid clinical deterioration of cardiac origin. Patients receiving bivalirudin did not show a significant reduction of the incidence of the primary end point (11.4  Long-term (6 and 12 months) clinical outcomes were similar in both groups. The Authors concluded that bivalirudin was non-inferior to UFH/GPI concerning the acute ischemic end points and was associated with a lower rate of major bleeding. To assess the superiority of bivalirudin compared with UFH in patients with stable or unstable angina who undergo PCI after pretreatment with clopidogrel the Intracoronary Stenting and Antithrombosis Research -Rapid Early Action for Coronary Treatment (ISAR -REACT) 3 study was performed. ISAR-REACT 3 was a multicenter double-blind randomized trial, designed to compare bivalirudin with UFH in patients undergoing PCI for stable or unstable angina 28 . The aim of this study was to compare bivalirudin with UFH in patients who had stable or unstable angina pectoris undergoing PCI and stenting after pretreatment with 600 mg of clopidogrel and aspirin (325 to 500 mg). The primary end point was the composite of death, myocardial infarction, urgent target-vessel revascularization due to myocardial ischemia within 30 days after randomization, or major bleeding during the index hospitalization (with a net clinical benefit defined as a reduction in the incidence of the end point). The secondary end point was the composite of death, myocardial infarction, or urgent target-vessel revascularization. No significant differences were observed between groups in primary and secondary end point (8.3 vs. 8.7%; RR, 0.94; 95% CI, 0.77 to 1.15; p=0.57; 5.9 vs. 5.0%; RR 1.16; 95% CI, 0.91 to 1.49; p=0.23). The incidence of major bleeding was prevalent in UFH group (3.1 vs. 4.6%; RR, 0.66; 95% CI, 0.49 to 0.90; p=0.008). In conclusion, in patients with stable and unstable angina undergoing PCI after preloading with clopidogrel, bivalirudin did not provide a net clinical benefit, but significantly reduced the incidence of major bleeding. The Novel Approaches for Preventing or Limiting EventS (NAPLES) trial was performed to evaluate bivalirudin safety and efficacy in the high risk subset of diabetic patients undergoing PCI. NAPLES was a single centre randomized trial focusing on the management of diabetic patients undergoing elective PCI pretreated with a loading dose of clopidogrel of 300 mg 29 . Patients were randomized to receive bivalirudin monotherapy or UFH plus routine tirofiban. The primary composite end point (30-day composite incidence of death, urgent repeat revascularization, myocardial infarction, and all bleedings) was lower in the bivalirudin group (18.0% vs. 31.5%, OR 0.47, 95% CI 0.28 to 0.79, p=0.004). No death, urgent revascularization, or Q-wave myocardial infarction were observed. The rate of non-Q-wave myocardial infarction was similar in the 2 groups (10.2 vs. 12.5%, p=0.606). A lower rate of any bleeding was observed in bivalirudin arm (8.4 vs. 20.8%, OR 0.34, 95% CI 0.18 to 0.67, p=0.002). This difference was mainly ascribed Università degli Studi di Salerno to the lower rate of minor bleeding (7.8 vs. 18.5%, OR 0.37, 95% CI 0.19 to 0.74, p=0.005), although the rate of major bleeding in the 2 groups was similar (0.6 vs. 2.4%, p=0.371). In conclusion, in patients with diabetes undergoing elective PCI, bivalirudin allows a reduction of in-hospital bleeding. To evaluate the effectiveness of bivalirudin versus UFH in selected PCI patients at high bleeding risk the Anti-Thrombotic Strategy for Reduction of Myocardial Damage During Angioplasty-Bivalirudin vs Heparin (ARMYDA-7 BIVALVE) was performed. ARMYDA-7 BIVALVE was a randomized open-label trial in patients at high bleeding, due to age >75 years, chronic renal failure, and diabetes mellitus, with documented coronary artery disease undergoing PCI risk 30 . Patients were randomized to bivalirudin (bolus 0.75 mg/kg followed by infusion during the procedure; n = 198) or UFH (75 IU/kg; n = 203), with provisional use of GPI during PCI. Patients undergoing primary PCI for STEMI were excluded. The primary efficacy and safety end point were the 30-day incidence of major adverse cardiac events (cardiac death, myocardial infarction, stent thrombosis, or target vessel revascularization), and the occurrence of any bleeding or entry-site complications after PCI, respectively. All patients were preloaded with clopidogrel 600 mg. No statistically significant differences between two groups were observed in major adverse cardiac event rate at 30 days (11.1 vs. 8.9%, p=0.56). The occurrence of the primary safety end point was lower in bivalirudin group (1.5 vs. 9.9%; p= 0.0001) and, this benefit, was essentially driven by the prevention of entry-site hematomas >10cm (0.5% vs. 6.9%, p=0.002). In conclusion, bivalirudin induces significantly lower bleeding and has a similar incidence of major adverse cardiac events in elderly patients, in patients with diabetes mellitus, or chronic renal failure undergoing PCI. Novel Approaches in Preventing and Limiting Events III Trial: Bivalirudin in High-Risk Bleeding Patients (NAPLES) III study assessed the safety and the efficacy of bivalirudin compared with UFH alone in the subset of patients at increased risk of bleeding undergoing elective PCI by femoral access. NAPLES III was a single-center double-blind trial comparing UFH to bivalirudin in patients undergoing elective PCI who had negative biomarkers but an high bleeding risk 31 . The primary endpoint was the rate of in-hospital major bleeding and no significant differences were observed among two groups (2.6 vs. 3.3%; p=0.54). The results of this randomized study suggested that there was no difference in major bleeding rate between bivalirudin and UFH in increased-risk patients undergoing transfemoral PCI. As suggested by latest ESC guideline on myocardial revascularization among PCI patients with negative biomarkers, bivalirudin reduced bleeding without affecting mortality and might therefore be considered for use in patients at high risk for bleeding 32 .

VI.
META-ANALYSES Several meta-analyses have been recently published in order to clarify the role of bivalirudin for patients undergoing PCI in different setting of patients.
Cavender and Sabatine performed a meta-analysis of 16 studies enrolling patients for planned PCI and randomly assigned to bivalirudin or heparin (UFH or low-molecular weight heparin) with or without a GPI 33 . The primary efficacy endpoint was the incidence of major adverse cardiac events up to 30 days. Secondary efficacy endpoints were death, myocardial infarction, ischemia-driven revascularisation, and stent thrombosis. The primary safety endpoint was major bleeding up to 30 days. Bivalirudin use was associated with an high risk of major adverse cardiac events (RR 1.09, 95% CI 1.01-1.17; p=0.0204), driven by an increases in myocardial infarction (1.12, 1.03-1.23) and ischaemia-driven revascularisation (1.16, 0.997-1.34) as compared with heparin, with no effect on mortality (0.99, 0.82-1.18). Furthermore, bivalirudin patients showed an increased risk of stent thrombosis (RR 1.38, 95% CI 1.09-1.74; p=0.0074), which was primarily due to an increase in acute cases in ST-segment elevation myocardial infarction (4.27, 2.28-8.00; p<0.0001). Moreover, bivalirudin patients showed lower major bleeding risk (RR 0.62, 95% CI 0.49-0.78; p<0.0001), but the magnitude of this effect varied greatly (p<0.0001) depending on whether GPI were used predominantly in the UFH arm only (0.53, 0.47-0.61; p<0.0001), provisionally in both arms (0.78, 0.51-1.19; p=0.25), or planned in both arms (1.07, 0.87-1.31; p= 0.53). In conclusion, the use of bivalirudin increases the risk of myocardial infarction and stent thrombosis, but decreases the risk of bleeding, with the magnitude of the reduction depending on concomitant GPI use. Current recommendations on the use of bivalirudin in patients treated with PCI are mostly based on trials comparing bivalirudin versus UFH plus planned GPI. Università degli Studi di Salerno Whether bivalirudin is also superior to UFH alone is still not well established. A meta-analysis of Cassese et al. investigates the efficacy and safety of bivalirudin versus UFH in patients treated with PCI without planned use of GPI 34 . The primary efficacy and safety outcomes were the 30-day incidence of death and major bleeding, respectively. The secondary outcomes were the 30-day incidence of myocardial infarction, definite stent thrombosis, urgent target vessel revascularization, and overall death at the longest available follow-up. Odds ratio (OR) and 95%CI served as summary statistics. At  . Non-fatal myocardial infarction was the most common presentation (83 %) of early stent thrombosis events, while death occurred infrequently (about 5 %). In conclusion, in patients undergoing PCI, bivalirudin compared to UFH is associated with a higher risk of early stent thrombosis, which is mainly related to more frequent acute events. Further studies are required to evaluate alternative strategies to mitigate this risk, without hampering the benefits derived from the reduction in bleeding events with bivalirudin. These meta-analyses substantially confirmed a reduction of bleeding, without a significant reduction of mortality rate in patients treated with bivalirudin; however a re-evaluation of current data adding MATRIX study patients demonstrate for the first time highly significant benefits of radial access in acute coronary syndrome patients for major adverse cardiovascular events (p= 0.0051) and all-cause mortality (p= 0.0011) in patients treated with bivalirudin 19 . In a recent meta-analysis, performed by Bavry AA et al. patients treated with bivalirudin, compared with those treated with UFH, showed a reduction of bleedings rate, but this difference was less significative when UFH dosage during PCI was reduced, or, when ACT control in the cathlab was performed for both study groups (UFH and Bivalirudin) 35 . Finally, as proposed by Navarese et al, comparing several anticoagulant regimen, a different approach based on an individualized hemorrhagic or ischemic risk assessment should be evaluate, performing a tailored therapy 36 .

VII. CONCLUSIONS
It is widely demonstrated that the use of bivalirudin in patients undergoing PCI due to acute coronary syndrome or stable angina significantly reduces incidence of major bleeding; however it is associated with a higher risk of early stent thrombosis, which is mainly related to more frequent acute events. MATRIX results, for the first time, demonstrated that death for all causes was reduced in patients treated with bivalirudin after a radial access. BRIGHT trial demonstrated that a prolonged bivalirudin administration significantly reduced the incidence of the early stent thrombosis. Further randomized clinical trials are needed to evaluate the safety and efficacy of bivalirudin in the era of PCI through radial artery with the use of new P2Y12 inhibitors and bioadsorbable scaffold even in high bleeding risk patients in which bivalirudin seems to be safe as reported in some case report 37 . Future approaches should be based on patient risk stratification in order to choose the best therapeutic option in each case with particular regard to the prevention of stent thrombosis. Finally, bivalirudin has higher cost compared to unfractionated heparin and it should be considered in the actual scenario of limited financial resources.